Submissions for variant NM_007294.4(BRCA1):c.3708T>G (p.Asn1236Lys)

gnomAD frequency: 0.00031  dbSNP: rs28897687

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083197	SCV001161511	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 6.81E-11
Invitae	RCV000048292	SCV000076305	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679692	SCV000108670	likely benign	not provided	2021-03-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10528853, 21965345, 22516946, 18375895, 26332594, 27495310, 23867111, 25637381, 21520273, 21702907, 24055113, 24728327, 16685647, 26727311, 11979449, 11149413, 20104584, 27616075, 33087888)
Ambry Genetics	RCV000131695	SCV000186731	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington	RCV000148395	SCV000190094	likely benign	Breast and/or ovarian cancer	2014-06-01	criteria provided, single submitter	research
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083197	SCV000195924	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-04-22	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000131695	SCV000267005	benign	Hereditary cancer-predisposing syndrome	2015-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048292	SCV000494417	benign	Hereditary breast ovarian cancer syndrome	2015-11-23	criteria provided, single submitter	clinical testing	Variant Summary: The BRCA1 c.3708T>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asn to Lys. 3/4 in-silico tools predict this variant to be benign. The composite observed allele frequency in controls, including the large and diverse ExAC cohort, is 29/121594 (1/4193); and the observed allele frequency in the Latino sub-population from ExAC population is 11/11570 (1/1052). These frequencies are not significantly different than the maximal expected allele frequency for a pathogenic BRCA1 variant (1/1000). However, the low frequency in control populations should still suggest that this variant is a rare polymorphism unless proven other. The variant has been cited to co-occur with various pathogenic BRCA1 and BRCA2 variants, including BRCA1 c.6944_6947delTAAA (p.Ile2315_Lys2316?fs), BRCA1 c.2722G>T (p.Glu908Ter), and BRCA2 c.8537_8538delAG (p.Glu2846Glyfs) from BIC and BRCA2 c.1310_1313delAAGA (p.Lys437IlefsX22) from UMD. These co-occurrence findings are a clear evidence that this variant is benign. Although the variant has been reported in multiple patients in the literature, the publications did not comprehensively rule out the presence of large rearrangements. LOH studies demonstrated the retention of wild type allele and the loss of the allele harboring this variant in tumors from 2 patients, further supporting a benign outcome (Osorio et al, 2002). In addition, a cell growth assay to measure this variant's ability to functionally complement BRCA1-deficient mouse embryonic stem cells showed the variant behaves like wildtype (Bouwman et al, 2013). Although clinical laboratories and databases are mixed in their classifications, the majority classify the variant as benign/likely benign/neutral. Taken together, this variant has been classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120300	SCV000538452	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 B/LB, 3 VUS
Department of Pathology and Molecular Medicine, Queen's University	RCV000120300	SCV000588047	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120300	SCV000593670	likely benign	not specified	2017-05-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083197	SCV000743404	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083197	SCV000744629	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679692	SCV000806939	likely benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000120300	SCV000864296	likely benign	not specified	2017-10-24	criteria provided, single submitter	clinical testing	BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Color Diagnostics, LLC DBA Color Health	RCV000131695	SCV000902607	benign	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000083197	SCV001140546	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679692	SCV001156768	benign	not provided	2023-10-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148395	SCV001333183	likely benign	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000048292	SCV002515203	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131695	SCV002538231	likely benign	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120300	SCV002760935	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477170	SCV002796176	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679692	SCV004140626	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP3, BP4, BS2
ITMI	RCV000120300	SCV000084452	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083197	SCV000115271	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083197	SCV000144842	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000083197	SCV000301434	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120300	SCV000587335	not provided	not specified	2014-01-31	no assertion provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353574	SCV000591464	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asn1236Lys variant has been previously reported in the literature in 11 of 5896 proband chromosomes with hereditary breast and ovarian cancer and was identified in 3 of 1510 control chromosomes included in these studies (Borg 2010, Diez 2003, Lara 2012, Osorio 2007, Simard 2007, Spurdle 2008, Weber 2006). The variant was also identified in dbSNP (ID: rs28897687), the GeneInsight COGR database (classified as with unknown significance by four clinical labs, and as likely benign by one clinical lab), ARUP Laboratories BRCA database (classified with uncertain significance), BIC database (35x with uncertain significance), LOVD, the ClinVar database (classified as having “uncertain significance” by three submitters; as “likely benign” by one submitter; and as “benign” by three submitters). The variant was also in 39 samples submitted to UMD, where it was classified as “neutral”. One of these samples had a co-occurring pathogenic BRCA2 variant (c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Asn1236Lys variant may not have clinical significance. In addition, the variant was identified at polymorphic frequencies in three HapMap populations: Han Chinese in Beijing (freq: 0.026), Japanese in Tokyo (freq: 0.012), and Toscans in Italy (freq: 0.011). The variant is not conserved in all mammals, and the variant amino acid Lys is present in purple sea urchin, increasing the likelihood that this amino acid position may not be functionally important. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. A study using a multifactorial-likelihood ratio model (co-occurrence, pathology and conservation) yielded inconclusive results for the classification of this variant (Spurdle 2008). One functional study found that the variant did not affect BRCA1 interstrand crosslink repair (Bouwman 2013), and another study using a minigene assay found that the variant did not affect normal splicing of the BRCA1 gene (Anczuków 2008 in Walker 2013). In addition, loss of heterozygosity analysis of tumours in two patients showed retention of the wild-type allele and loss of the allele in which the variant was located, confirming that the variant was not deleterious (Osorio 2002). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083197	SCV000733622	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679692	SCV001905706	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679692	SCV001957821	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083197	SCV004244031	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing